Abstract Intrinsically disordered proteins (IDPs) are crucial components of normal cellular function and act as integrators of signaling and as hubs in protein networks. Disordered proteins are disproportionately associated with pathologies, especially cancer (e.g., c-Myc, p53) and neurodegenerative disease (e.g., tau, ?-synuclein) suggesting that the development of new and general rules for targeting IDPs could have a broad impact on human disease. Small molecules can bind to IDPs and disrupt their normal function. This proposal seeks to test the hypothesis that small molecules can bind specifically to intrinsically disordered protein sequences through distributing affinity among a set of residues that remain dynamic during binding. This contrasts with structured targets that typically have affinity concentrated in a small number of well-ordered hot-spots. The specificity of a small molecule that targets IDPs would be determined largely by the number of these affinity-determining residues that are required to achieve binding, building specificity through the combination of multiple determinants all of which are necessary but alone or in subsets are not sufficient. The ability to deal with IDPs at the primary sequence level has great potential, however, we do not currently have any effective means of determining what IDP sequences would likely support specific binding. Hence screening is done blind and in successful screens determining the actual small molecule binding site on an IDP has been difficult. The proposed studies will provide insight into sequence characteristics of binding sites such as the types of residues that are important, those that are tolerated, and those that are disfavored, as well as the degree of clustering of required residues.